Phorbol myristate acetate (PMA) and related diterpene esters are among the most potent tumor promoters and/or inflammatory agents known. Recently, they have also been shown to cause terminal differentiation of human myeloid leukemia cell lines, HL-60 and KG-1, and to induce them to express a monocyte/macrophage phenotype. We propose to examine the various types of human blood cells for the presence of specific receptors for PMA and related compounds. These receptors will be characterized and the rate or extent of their occupancy will be correlated with cellular response(s) to PMA exposure. We will also examine and characterize the PMA receptor(s) of HL-60 and HG-1 human myeloid leukemia cells, and correlate these properties with the induction of terminal differentiation. The studies will use receptor-binding methodology recently developed in our laboratory and successfully applied to normal human neutrophils. These preliminary studies showed that human neutrophils contained specific receptors for PMA and that the rate and extent of receptor occupancy controlled different aspects of the "respiratory burst". We will extend this type of analytical approach to another aspect of the inflammatory process, degranulation, and to the induction of terminal differentiation in leukemic cell lines. In the latter studies, we will attempt to select and clone myeloid mutants that are resistant to one or more cellular effects of PMA. Our long range goals are to evaluate the biochemical and regulatory behavior of PMA-receptors in human blood cells and to establish their functional significance.